Teledentistry: A Future Solution in the Diagnosis of Oral Lesions: Diagnostic Meta-Analysis and Systematic Review

Introduction: Teledentistry (TD) can offer a wide range of possibilities in the field of oral medicine. Oral potentially malignant disorders (OPMDs) are hard to detect, and even harder to diagnose correctly. With the help of TD, OPMDs can be detected and diagnosed by a remote specialist. Our aim was to investigate whether TD could provide a reliable diagnostic method compared with clinical oral examination (COE) in the diagnosis of OPMDs. Methods: A systematic search was conducted in three databases (Medline, EMBASE, CENTRAL) until November 2021. We included studies that compared telediagnosis and COE, both made by experts. Pooled specificity and sensitivity were calculated and visualized on a two-dimensional plot. Risk of bias was assessed using the QUADAS-2 tool, and the level of evidence is shown with the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) tool. Results: Of the 7,608 studies, 13 were included in the qualitative and 9 in the quantitative synthesis. Using TD tools in the detection of oral lesions (OLs) showed high specificity (0.92 confidence interval [95% CI] = 0.59–0.99) and sensitivity (0.93 95% CI = 0.17–1.00). In the differential diagnosis of lesions, we found high sensitivity and specificity (0.942 95% CI = 0.826–0.982 and 0.982 95% CI = 0.913–0.997), respectively. We summarized the available data on time-effectiveness, screening person, referral decision, and technical settings. Conclusion: Detecting OLs with TD tools might lead to earlier diagnosis, treatment, and stricter follow-up of OPMD. TD may offer a great substitution for COE in the diagnosis of OLs, and thus, fewer referrals could be made to special care, resulting in a greater number of treated OPMDs.


Introduction
T eledentistry (TD), as part of telemedicine, is an information technology-based diagnosis, treatment, and education delivery system in the dental field. 1 The recent rise of the use of TD due to COVID-19 has shown its potential for implementing different solutions to primary dental care. 2 TD involves store-and-forward (SAF) solutions, which allow the patient-doctor communication to take part both at different time points (e.g., via a chat application) and in realtime (RT) solutions that require both the patient and the doctor to be simultaneously present in the online space (e.g., videoconference).Through these solutions, the transfer of electronic health records, teleconsultation, telediagnosis, online therapy planning, follow-up, remote patient monitoring, online research, and tele-education can be applied to dentistry. 1 As visual information can include important details about a clinical case, a photograph-based telediagnosis depends on image resolution. 3Teledermatology, where evidence for telediagnosis is based on image capturing, is one of the most investigated and developing fields in telemedicine. 4Recent research in teledermatology shows contradictory findings about the diagnostic accuracy of the field, 5,6 however, this research has not yet been performed in oral medicine (OM).
The correct diagnosis of premalignant lesions is essential.Due to the fact that oral cancer (OC) in an early stage is asymptomatic, it lacks patient-reported symptoms: ulceration, bleeding, and induration. 7In developing countries such as India and Malaysia where smokeless tobacco (e.g., betel chewing) is popular, the problem arises. 8Other risk factors can include infections, solar radiation, dental hygiene, and genetic factors. 8A low-resource setting and the lack of specialists in rural areas lengthen the diagnosing procedure, allowing the manifestation of oral potentially malignant disorders (OPMDs).TD could help in bridging this problem.Providing high-risk populations with a general oral mucosa screening could decrease the rising amount of OC.
Diagnosing oral lesions (OL) can be difficult due to the variability of presence and the lack of training in OM. 9 Detection and follow-up of OPMDs at an early stage could stop their manifestation to OC.Also, the similarities between precancerous lesions and some benign lesions cause difficulties in differential diagnosis. 7Therefore, many unnecessary referrals are made by primary dentists to OM specialists, resulting in wait time and travel difficulties for patients. 10D has the potential to connect patients with dentists via the online space, thus improving access to care in rural areas. 11his systematic review and meta-analysis aimed to collect available data on how OM could benefit from TD solutions.Due to the lack of data about different TD tools and concise data about the use of TD in OM, an extended summary is needed.
Our aim is to investigate the existing TD tools in the diagnosis of OLs using clinical oral examination (COE) as a reference standard.The main outcome is the presence and the differential diagnostic accuracy of OPMDs, which can lead to lowering the number of referrals to special care.

Methods
Reporting of this systematic review and meta-analysis is based on the recommendation of the PRISMA 2020 guideline, 12 while we followed the Cochrane Handbook. 12The protocol of the study was registered on PROSPERO (registration number CRD 42021282645) with no deviations from it.

SEARCH STRATEGY AND ELIGIBILITY CRITERIA
The systematic search was conducted on October 25, 2021, and was revised on October 11, 2022, in the following electronic databases: MEDLINE (via PubMed), Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL).The search key we used in each database is detailed in Supplementary Data S1.
The search applied no filters.Only English language articles were considered eligible.In addition, the reference lists of eligible studies were also searched.Nonoriginal articles (reviews, editorials, letters, and comments) and nonpeerreviewed articles (gray literature) were excluded.In vitro and animal studies were also excluded.
Study eligibility was determined based on the PICO framework: adults with suspected OLs (P), who were examined using TD tools (that included imaging, I) were acceptable with a reference standard (C) of COE or biopsy.Specificity and sensitivity, positive predictive value (PPV), and negative predictive value (NPV) were considered the included outcomes (O).Regarding the study type, observational studies were considered eligible.

SELECTION PROCESS
The selection was performed by two independent review authors (E.U. and Z.D.).After the duplicates were removed using reference management software (EndNote X9, Clarivate Analytics), the two authors independently screened titles, abstracts, and then full texts.Disagreements were resolved by a third independent reviewer (O.N.).

DATA COLLECTION PROCESS
Data were collected by two authors independently (E.U. and Z.D.) based on a predefined data collection form.The disagreements were resolved by a third independent author (O.N.).
The following data were extracted: first author, year of publication, type of study, country, study population, mean age, surveyed risk factors, number of participants, target condition definition, person conducting telediagnosis, type of photography tool, description of TD tool, and reference standard.

DIAGNOSTIC ACCURACY MEASURES
The comparison of a new diagnostic test (TD) with the gold standard of the field (COE) is conventionally summarized in a two-by-two table called the diagnostic contingency table.It contains the numbers of true-positive (TP), false-positive (FP), true-negative (TN), and false-negative (FN) cases.The most common measures calculated based on the table include sensitivity, specificity, accuracy, and PPV and NPV.All these data were collected in a predefined data table.

ORAL PREMALIGNANT OR MALIGNANT DISEASE
We established a detailed diagnosis classification table based on Haron's predefined list 13 to define OPMD lesions in those articles that have only the final diagnosis listed.We considered the WHO classification of OLs 14 as the standard decision base in cases of questionable diagnosis.The final table was discussed with an OM expert (O.N.).

RISK-OF-BIAS ASSESSMENT
Based on the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy, 12 we used the QUADAS-2 tool 15 for risk-of-bias assessment.This was performed by two review authors (E.U. and Z.D.).Disagreements were resolved by a third independent author (O.N.).

CERTAINTY OF EVIDENCE
Certainty of evidence was evaluated based on the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) workgroup's recommendations. 16The endpoints of the outcomes were assessed by two independent reviewers (E.U. and Z.D.).In case of disagreement, a third independent reviewer resolved it (O.N.).
We made the GRADE evidence profiles with GRADEpro GDT Software 17 for the investigated outcomes.

SYNTHESIS METHODS
Two by two contingency tables were extracted from the studies containing TP, FP, FN, and TN values.Where studies published data corresponding to more than one remote expert, we randomly selected one of them.We repeated the analysis using the contingency tables of previously nonselected experts as a sensitivity analysis.
We used the bivariate model of Chu and Cole and Reitsma et al. 18,19 Ellipsoids of this analysis reflect the weights of the studies according to the method by Burke et al. 20 Univariate analyses of sensitivity and specificity were performed using the generalized mixed-effect approach. 21Statistical analyses were carried out using the online tool described in Freeman et al. 22 and the meta package of R statistical software (version 4.1.2.).The statistical analyses followed the advice of Harrer et al. 23 Further details of the synthesis methods are described in Supplementary Data S2.

SEARCH AND SELECTION
7,28,33 The selection process and Cohen's kappa values are presented using a PRISMA flowchart (Fig. 1).

BASIC CHARACTERISTICS OF INCLUDED STUDIES
The baseline characteristics of the studies included in the qualitative analysis are detailed in Table 1.

PRIMARY OUTCOMES
Oral lesion detection with TD tools.Our pooled analysis of 3 articles 3,13,24 including 3,783 patients showed that TD tools can be a reliable option for replacing face-to-face dental visits in the detection of OLs (sensitivity: 0.92 confidence interval [CI] = 0.59-0.99;specificity: 0.93 CI = 0.17-1.00)(Fig. 2).The data used for this analysis are shown in Supplementary Table S1.The examined outcome showed a substantially heterogenous population (sensitivity: I 2 = 84%, p < 0.01; specificity: I 2 = 98%, p < 0.01).Fitting the bivariate model was not possible in this analysis due to the small number of available studies.
Diagnosing oral premalignant lesions or oral cancer.As the exact number of TP, TN, FP, and FN lesions was not mentioned in every article, the abovementioned classification table was able to help us resolve the problem, as can be seen in Supplementary Table S2.
Conducting sensitivity analysis, the resulting sensitivity and specificity are 0.953 (CI = 0.856-0.986)and 0.983 (CI = 0.930-0.996),respectively.See Supplementary Data for further details of the extractions (Supplementary Table S4).This result confirmed the findings of the main analysis; thus, the

USE OF TELEDENTISTRY IN ORAL MEDICINE
outcome shows that the results do not depend on the examiner's knowledge (Supplementary Figs.S2 and S3).

SECONDARY OUTCOMES
Time-effectiveness.No statistical analysis could be performed on time-effectiveness due to the heterogeneity of reported data.Namakian et al. 28 measured the difference in time during in-person examination (mean: 4.2 min, SD: 1.6) and virtual examination (2.83 min, SD: 1.0).Perdoncini et al. 29 listed the transportation time (mean: 58.3 min, SD: 52.9), which shows that mostly people from rural areas attended the clinic.The COE took 10.44 min on average (SD: 2.88).In the case of the WhatsApp messaging platform, Petruzzi and De Benedittis 10 measured an average distance of 70 km (SD: 78 km).
Screening person.Birur et al. 25 showed that a trained frontline health care worker could detect OPMD with a PPV of 45%.They also studied the efficacy of community health care workers (CHWs) in the diagnosis of the presence of OL, where they found a kappa score of 0.92 between CHWs and onsite specialists. 24herefore, not only dentists but also trained CHWs could take part in the detection of OLs.
Referral decision.The referral decision was measured in four articles, 3,13,27,28 however, its policy showed variability.Fonseca et al. 27 recorded that an average of 35.4% of the examined patients could be treated in primary dental care.Haron et al. 13 recorded a kappa value of 0.892 (CI: 0.843-0.940)for referrals using a predefined list.
Technical setting.The technical setting of TD tools varied in the available articles.Haron et al. 3 found a correlation between using better resolution mobile phones as photograph-taking devices in diagnosing lesion category: the higher the resolution, the higher the diagnostic agreement (accuracy: 0.515-0.881).Using a better mobile phone helped not only in better detection (sensitivity: 0.813), but also in correct diagnosis (sensitivity: 0.93).
Perdoncini et al. 29 investigated the accuracy of RT video consultation with a specialist; 91% of the photographs were of good quality, and the internet connection was stable in 58% of the cases.
A professional camera was used in two articles 31,32 to simulate primary dental care settings.The images then were sent to the specialist via e-mail, thus avoiding internet connection problems.UHRIN ET AL.Receiving photographs and testing the role of free chat applications in dentistry can simulate population-based screening. 10,29,33Not only dentists, but also dental hygienists and patients sent homemade photographs of OLs.WhatsApp was tested by Vinayagamoorthy et al., 33 where a sensitivity of 0.981 (examiner 1) and 0.987 (examiner 2) was found for exact lesion diagnosis.

RISK-OF-BIAS ASSESSMENT
Using the QUADAS-2 tool, 15 our results for risk-of-bias assessment are presented in Supplementary Figures S4, S5, and S6.Most of the domains showed low risk of bias, however, having inappropriate exclusion criteria in patient selection in one article meant that only people with risk factors were involved in the actual study, 27 and in another study, the patients were selected by having/not having OL/OPMD/OC. 3 The index test result domain has unclear risk in those articles where COE (index test) was made by the same person who made the telediagnosis with a fixed, predefined washout period. 27,28,30ue to the small number of available studies, publication bias could not be assessed by performing the methodology of Deeks et al. 35 Certainity of evidence Table can be seen in Supplementary Table S5.The PRISMA checklist can be seen in Supplementary Table S6.

Discussion
According to the high sensitivity and specificity in our study, TD could successfully help in primary dental care in the field of OM.Store-and-forward systems could be used in telediagnosis (e.g., photographs sent via e-mail), and RT solutions could be used in teleconsultation (e.g., video consultation). 29isual examination is extremely important (and remains the primary diagnostic tool) in both dermatology and OM, causing a rapid technical rise in both teledermatology and TD. 36Image-based diagnosis by a specialist may help primary dental care facilities in the decision of referral to special care.Also, TD could promote organizing population-based OL screening programs in the future. 25The differential diagnosis of OLs is important due to treatment planning reasons.TD could support general dentists in OL management through connection with OM specialists, enabling early diagnosis and correct treatment of oral (pre)malignant lesions. 34,36,37nowing the best available treatment and prevention could lead to less manifestation of OC.Furthermore, referring only OPMDs and malignant OLs might result in a higher percentage of treated patients.
As the prevalence of OC is rising, the correct diagnosis of premalignant lesions is essential.In developing countries, low-resource settings and the lack of specialists in rural

USE OF TELEDENTISTRY IN ORAL MEDICINE
areas make the diagnosing procedure longer, allowing manifestations of OPMD.TD could help in solving this problem.
TD tools in the diagnosis of OLs show high accuracy, however, there are weaknesses in the available data that need to be mentioned.The protocol of diagnosis by the same person was followed by several articles, which despite the washout time (average 3 weeks) still brings into question the reliability and correctness of the results. 3,13,28,33Also, in one case, the general dentist could send his or her own diagnostic opinion, compromising the impartiality of the diagnosis. 30ducation in the field of OM starts during the predoctoral phase, however, it varies afterward.A huge difference can be spotted regarding specialists: for example, in the United States, this field is a recognized dental specialty of the American Dental Association, 38 however, in Europe, it varies from country to country, and a consensus has not been made yet about the competencies and limits of OM specialists. 39This fact questions the use of the term OM ''specialist'' in the articles.In addition, experience in the field does not guarantee a correct diagnosis using TD tools.Lack of information in the online form and the lack of in-person personalized questions may complicate the diagnosing process.
Referring every patient with an OL to special care might overload OM praxis.A high number of referrals may be avoidable using a pretriage system 40 or population-based screening. 24This could increase the efficacy of patient flow in OM practices.

OL DETECTION
OC is unique compared with other cancers because visual detection at an early stage is possible with COE, 41 however, we cannot predict the level of dysplasia based on clinical images.Diagnosing the presence and type of OL could lead to targeted treatment and prevention of manifestation to OC. 41 Our results showed both high specificity and sensitivity in the detection of OLs, meaning that TD tools could be used as a pretriage system in the diagnosis of OLs.

DIFFERENTIAL DIAGNOSIS OF OLS
Correct diagnosis of an OL is necessary before treatment, however, not all patients need to be referred to an OM specialist.Our study showed high sensitivity, meaning that TP OPMD could be successfully diagnosed via TD image-sharing tools (e-mail, free chat applications, cloudbased storage applications, etc.).We found high specificity, meaning that TN lesions that do not necessitate referral to a specialist are correctly diagnosed, affirming previous articles' clinical data. 3,13

STRENGTHS
According to our knowledge, this is the first meta-analysis on this specific topic.We used rigorous methodology and followed a previously registered protocol.We selected for eligibility only those articles in which the clinical diagnosis (reference standard) was made only by doctors.Due to the strict inclusion criteria, we gained higher data quality (e.g., we excluded articles that did not include a reference standard).We did not include publications with retrospective or casecontrol designs.

LIMITATIONS
Regarding the limitations of this article, within the available data regarding the detection of OLs, we found significant heterogeneity among the included articles.The reason for this, despite the strict inclusion criteria, could be the included heterogenous population (e.g., a preselected population or factory workers).The methodology of applied TD tools was heterogeneous, meaning that RT and SAF systems were pooled together.The referral decision was not defined in each of our selected articles, and so, we could not include it in a quantitative analysis.

IMPLICATION FOR PRACTICE
A future photograph-taking protocol for OLs could be used in primary dental care.We suggest establishing the technical setting first, as telecommunication tools require a firm technical background.Also, a standardized questionnaire could be used in the future to provide more details about the patient.

IMPLICATION FOR RESEARCH
We suggest that researchers use biopsy as a reference standard (replacing COE) to have an objective diagnosis.Furthermore, exact lesion diagnosis could be helpful in comparison with other publications' results, and referral decisions could be counted based on these data.

Conclusions
Detecting OLs with TD tools could lead to early diagnosis, treatment, and stricter follow-up of OPMDs.TD offers a great substitute for face-to-face dental visits in the detection and differential diagnosis of OLs, and thus, fewer referrals could be made to special OM care.Being a time-effective solution, when conducted in a proper way, access to care could be widened with the use of these tools.

Fig. 2 .
Fig.2.Sensitivity and specificity of diagnosing the presence of oral lesions with teledentistry tools.CI, confidence interval; TP, true positive; TN, true negative.

Table 1 .
Characteristics of the Studies Included in Qualitative Analysis M A R Y A N N L I E B E R T , I N C .VOL. 29 NO.11 NOVEMBER 2023 TELEMEDICINE and e-HEALTH 1595

Table 1 .
Characteristics of the Studies Included in Qualitative Analysis continued a Study included only in systematic review.COE, clinical oral examination; OPMDs, oral potentially malignant disorders.